This invention is directed to aralkyl esters (more preferably alkaralkyl esters) of salicylic acid and their use in treating aspirin or ibuprofen-treatable conditions. This invention is also directed at hydroxymethylacylfulvene analogs and their use as antitumor drugs.
Aspirin (acetylsalicylic acid), one of the oldest over-the-counter drugs having been marketed since 1899, continues to be used for relief from headaches, fevers and arthritis pain. Aspirin works as an analgesic to reduce pain, an anti-pyretic to reduce fever and an anti-inflammatory agent. Recently, aspirin has been shown to aid in the prevention of heart attacks. However, aspirin does have undesirable side effects. Use of aspirin has been linked to Reye""s Syndrome in children, hearing impairment in heavy users, stomach problems, excessive bleeding and certain rare but serious complications of pregnancy.
Other anti-inflammatory drugs that reduce pain such as acetaminophen (under the trade name Tylenol) and ibuprofen (under the trade names Motrin, Advil and Nuprin) are also available. However, these also are associated with potentially harmful side effects. Acetaminophen, the most preferred analgesic after aspirin, can cause delayed liver damage when used excessively and major kidney damage with long-term chronic use. Accordingly, there is still a need for analgesic, anti-pyretic and anti-inflammatory drugs that can be used in place of aspirin, ibuprofen and acetaminophen.
A listing of human cancers for which chemotherapy has exerted a predominant role in increasing life span, approaching normal life expectancy, includes Burkitt""s lymphoma, acute lymphocytic leukemia and Hodgkin""s disease, along with about 10-15 other tumor types. See, for example, Golden et al., Eur. J Cancer, 12, 129 (1981) (Table 1). While the cure rate of these cancers illustrates the level of success of screening systems in selecting antitumor agents that are effective in man, these responsive tumors represent only a small fraction of the various types of cancer and, notably, there are relatively few drugs highly active against clinical solid tumors. Such drugs include cyclophosphamide, adriamycin, 5-FU, hexamethylmelamine and the like. Thus, patients with many types of malignancies remain at significant risk for relapse and mortality.
After relapse, some patients can be reinduced into remission with their initial treatment regimen. However, higher doses of the initial chemotherapeutic agent or the use of additional agents are frequently required, indicating the development of at least partial drug resistance. Recent evidence indicates drug resistance can develop simultaneously to several agents, including ones to which the patient was not exposed. The development of multiple-drug resistant (MDR) tumors may be a function of tumor mass and constitutes a major cause of treatment failure. To overcome this drug resistance, high-dose chemotherapy with or without radiation and allogenic or autologous bone marrow transplantation can be employed. The high-dose chemotherapy may employ the original drug(s) or be altered to include additional agents. The development of new drugs non-cross resistant with MDR phenotypes is required to further the curative potential of current regimens and to facilitate curative interventions in previously treated patients.
Recently, the in vitro anti-tumor activity of a novel class of natural products called illudins has been examined. See Kelner et al., Cancer Res., 47, 3186 (1987). The extreme toxicity of illudins has prevented any applications in human tumor therapy. Recently, synthetic analogs of the illudins have been developed which exhibit promising antitumor activity. See, for example, U.S. Pat. No. 5,439,936 (Kelner et al), issued Aug. 8, 1995 and U.S. Pat. No. 5,523490 (Kelner et al), issued Jun. 4, 1996. These include hydroxymethylacylfluvene (HMAF) which has recently shown promise as an antitumor drug. See Zurer, Chem. Eng. News, page 7 (Feb. 10, 1997) However, there still exists a continuing need for chemotherapeutic agents which inhibit tumor growth, especially solid tumor growth, and which have an adequate therapeutic index to be effective for in vivo treatment.
The present invention relates to ibuprofen-aspirin compounds useful in treating various conditions previously treated with aspirin or ibuprofen and which have the formula I: 
wherein R1 is hydrogen, benzoyl or alkyl, e.g., lower alkyl of 1 to 6 carbon atoms, and preferably is a branched chain alkyl, e.g., isoalkyl, sec-alkyl or tert-alkyl; R2 and R3 are hydrogen or lower alkyl, e.g. methyl, ethyl or propyl, preferably R2 is hydrogen and R3 is methyl; n is zero or a small integer, e.g., 1, 2, or 3; R4 and R5 are hydrogen or lower alkyl, preferably hydrogen or methyl; R6 and R7 are as defined for R1 and are preferably hydrogen; and X is hydrogen or a pharmaceutically acceptable salt forming metal or group (advantageously, the sodium, potassium, lithium, calcium or ammonium salts). When R1 is alkyl, it is preferably in the para position but can be in the ortho or meta position. When R1 is benzoyl, it is preferably in the meta position. An example of such a compound is the phenolic acid ester of ketoprofen(2-(3-benzoylphenyl)-propionic acid.
The present invention also relates to hydroxymethylacylfulvene analog compounds useful as antitumor drugs and which have the formula II: 
wherein R8 is an acyl group of an acid having at least 3 carbon atoms, the acid being selected from alkenoic acids having 1 to 6 ethylenic double bonds, phenoxyalkanoic acids, ring halogenated phenoxyalkanoic acids having 1 to 3 ring halogen atoms, alkylidene bis-phenoxyalkanoic acids and alkylidene bis-ring halogenated phenoxyalkanoic acids having 1 to 3 ring halogen atoms in each ring; R9 is hydrogen, an alkyl group having 1 to 4 carbon atoms, or an acyl group having 1 to 4 carbon atoms, preferably hydrogen; each R10, R11, and R12 is an alkyl group having 1 to 4 carbon atoms, preferably a methyl group; and pharmaceutically acceptable salts thereof.